The lactogenic hormones, prolactin (PRL) and placental lactogen (PL), which signal through the prolactin receptor, are important for islet development, for enhancing beta cell proliferation, and for improving islet function in normal physiology as well as during pregnancy. We have developed a transgenic mouse model in which the rat insulin II promoter (RIP) drives expression of murine placental lactogen I (mPL1) cDNA in beta cells. These mice are hypoglycemic and display islet hyperplasia as a result of increased beta cell proliferation and hypertrophy. Although activation of the prolactin receptor improves survival in a number of different cell types, the effect of lactogens on beta cell survival has just begun to be examined. In this context, we have recently demonstrated that PL expression in the beta cell of RIP-mPL1 mice confers resistance to the diabetogenic and cytotoxic effects of streptozotocin in these mice, implying a protective role of mPL1 in beta cells. However, nothing is known regarding the nature, mechanism, and signaling pathways implicated in the protective effect of lactogens on beta cells. Understanding the regulation of beta cell survival is important both in normal physiology, as well as in the pathophysiology of diabetes and islet transplantation. Therefore, the main goals of the current proposal are to understand how lactogen signaling can enhance beta cell survival, to determine the relevance of this pathway in the survival of beta cells under physiological and pathophysiological conditions, and to examine whether the beneficial effects of these hormones can translate into enhanced performance in islet transplantation. The Specific Aims of this proposal are: 1) To define the mechanisms responsible for lactogen-induced survival of beta cells. 2) To establish the physiological significance of lactogen signaling on beta cell survival. 3) To examine the role of lactogens in islet transplant outcomes. The studies in this proposal will further our understanding of the regulation of beta cell death by lactogens. The ultimate objective is to apply this knowledge to select suitable candidate genes for prolonging islet survival in future therapeutic studies in the context of islet transplantation and in the prevention and cure of diabetes.